Aquaporin 5 is degraded by autophagy in diabetic submandibular gland

Abstract

Autophagy is a catabolic process which is involved in the development of many diseases including diabetes mellitus and its complications. Hyposalivation is a common complication of diabetes mellitus, whereas its mechanism remains unclear. Here, we observed that the stimulated salivary flow rate of SMG was significantly decreased in db/db mice, a diabetic mice model. The expressions of aquaporin 5 (AQP5), a water channel protein, were decreased, whereas the mRNA level of AQP5 was increased in SMGs of both diabetic patients and mice. Under transmission electron microcope, more autophagosomes were detected in diabetic SMGs. Expressions of autophagy related proteins LC3II, Beclin-1 and ATG5 were increased, meanwhile autophagy substrate p62 was decreased in SMGs of diabetic patients and mice, indicating that autophagy was activated in diabetic SMG. Double immunofluorescence staining showed that the colocalization of AQP5 and LC3 was increased in SMGs of diabetic mice. In cultured SMG-C6 cells, high glucose (HG), but not high osmotic pressure, reduced AQP5 protein expression and induced autophagy. Moreover, inhibition of autophagy by 3-methyladenin, an autophagy inhibitor, or by autophagy-related gene 5 siRNA, decreased HG-induced AQP5 reduction in SMG-C6 cells. Additionally, the expression of p-p85, p-Akt and p-mTOR were decreased in HG-treated SMG-C6 cells. Pretreatment with 740Y-P, a PI3K agonist, significantly suppressed HG-induced autophagy and AQP5 degradation. Taken together, these results indicate that autophagy plays a crucial role in AQP5 degradation in diabetic SMG via PI3K/Akt/mTOR signaling pathway, which contributes to the dysfunction of diabetic SMG. Our study provides a novel mechanism of diabetic hyposalivation.

Disruption of tight junctions contributes to hyposalivation of salivary glands in a mouse model of type 2 diabetes

“…Saliva is mainly secreted from three major salivary glands namely the submandibular glands (SMGs), parotid glands (PGs), and sublingual glands (SLGs) through a tight junction (TJ)‐based paracellular pathway and an aquaporin 5 (AQP5)‐mediated transcellular pathway (Liu and Lin, 1969). Recently, reduced expression of AQP5 has been reported in diabetes patients and animal models (Zhang et al , 2013; Huang et al , 2018); however, little is known about the changes in the paracellular pathway in diabetes salivary glands. TJs are the protein complex located at the cell‐to‐cell interactions, which consist by transmembrane proteins, such as claudins (Cldns) and occludin (Ocln), together with intracellular proteins, like zonula occludens (ZOs) (Zhang et al , 2018).…”

A Combination of UPLC-LTQ-Orbitrap-MSn Research, Network Analysis and Experimental Verification Used to Explore the Mechanism of Yangyin Yiqi Huoxue Recipe in Treating Sjogren’s Syndrome

“…AQP5 is an important protein that mediates the rapid transcellular transport of water in salivary gland cells [20] . AQP5 contributes to salivary secretion in patients with SS [21] . Abnormal distribution of AQP5 in labial salivary glands is associated with poor saliva secretion in patients with SS, including patients with the complication neuromyelitis optica.…”

“…Abnormal distribution of AQP5 in labial salivary glands is associated with poor saliva secretion in patients with SS, including patients with the complication neuromyelitis optica. In the submandibular glands (SMG) of patients and mice with diabetes, the expression of AQP5 is reduced, which leads to the dysfunction of diabetic SMG, and saliva production decreases [21] .…”

LncRNA and mRNA expression profiles and functional networks of hyposalivation of the submandibular gland in hypertension

“…The rats were fasted randomly for 12 h. After anaesthesia with an intraperitoneal injection of chloral hydrate (0.4 g/kg body weight), the SMG duct was isolated and inserted into a capillary tube. The volume of saliva was measured 10 min after the injection of pilocarpine (10 μg/kg body weight) 21 .…”